Oral 13-cis-retinoic acid was effective in the treatment of skin cancer, and a variety of disorders of keratinization (lamellar ichthyosis, Darier's disease, pityriasis rubra pilaris), and cystic acne. An oral synthetic aromatic derivative of retinoic acid (RO-10-9359) was more effective and less toxic than 13-cis-retinoic acid in the treatment of the disorders of keratinization. A high initial followed by a low maintenance dosage of 13-cis-retinoic acid was comparably effective but less toxic than previously used continuous high-dosage schedules in the treatment of cystic acne. The high-low dosage schedule was superior to the high initial dose schedule used alone and to a continuous low dose schedule. 13-cis-retinoic acid led to small but significant elevations in plasma lipids and changes in lipoproteins during therapy. RO-10-9359 produced similar changes which were dose dependent and responsive to dietary management. Absorption of RO-10-9359 is greater with milk as a source of long-chain fatty acids, than with water. Etretinate is bound in plasma to beta-liproproteins. Administration of etretinate with milk vs. water yielded different ratios of drug to metabolite in the serum. Etretinate persists in the serum after discontinuation of therapy and trace amounts have been directed after more than 2 years. Etretinate is stored in fat and serum etretinate concentration correlates with percent of ideal body weight. One chronic toxicity, "retinoid hyperostosis", has been observed with long-term, high-dose isotretinoin characterized by anterior spinal ligament calcification and osteophyte formation of vertebrae.